Flotillin-mediated stabilization of unfolded proteins in bacterial membrane microdomains

Marta Ukleja, Lara Kricks, Gabriel Torrens, Ilaria Peschiera, Ines Rodrigues-Lopes, Marcin Krupka, Julia García-Fernández, Roberto Melero, Rosa Campo, Ana Eulalio, André Mateus, María López-Bravo, Ana I. Rico, Felipe Cava and Daniel Lopez ()
Additional contact information
Marta Ukleja: Spanish National Research Council (CNB-CSIC)
Lara Kricks: Spanish National Research Council (CNB-CSIC)
Gabriel Torrens: Umeå University
Ilaria Peschiera: Spanish National Research Council (CNB-CSIC)
Ines Rodrigues-Lopes: University of Coimbra
Marcin Krupka: Spanish National Research Council (CNB-CSIC)
Julia García-Fernández: Spanish National Research Council (CNB-CSIC)
Roberto Melero: Spanish National Research Council (CNB-CSIC)
Rosa Campo: Ramón y Cajal Hospital
Ana Eulalio: University of Coimbra
André Mateus: The Laboratory for Molecular Infection Medicine Sweden (MIMS). Umeå Center for Microbial Research (UCMR). Science for Life Laboratory (SciLifeLab)
María López-Bravo: Spanish National Research Council (CNB-CSIC)
Ana I. Rico: Spanish National Research Council (CNB-CSIC)
Felipe Cava: Umeå University
Daniel Lopez: Spanish National Research Council (CNB-CSIC)

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

Date: 2024
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DOI: 10.1038/s41467-024-49951-1

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